In the current PAGE study (PAGE 1) we investigated many genetic loci identified through genome-wide association studies (GWAS) in ancestrally diverse populations, and successfully generalized and fine-mapped many GWAS loci from studies of European-descent populations. These successes support extending the genomic search to less frequent and rare variants, which have not been captured in GWAS, but represent the largest fraction of genetic variation in the genome and contribute to the heritabilit of many complex traits. Most GWAS have been conducted in Europeans; yet studies investigating the impact of genetic risk factors, including low frequency variants, on common complex traits in diverse populations are needed including understudied US minorities having high burden of disease. The goal of this project is to comprehensively investigate less frequent and rare non-synonymous variants across the protein coding regions of the genome, i.e. the exome, and their associations with common complex traits, such as cardiovascular disease, cancer, body composition, blood lipids, glucose, insulin, and many other outcomes in a multi-ethnic population. Specifically, we propose to use a newly developed ExomeChip genotyping platform, augmented with additional content focused on ancestral diversity and putative regulatory elements in non-coding regions. This platform is highly cost-efficient and will provide genotyping data on about 350,000 variants with allele frequencies as low as 0.1%. Most of these low frequency variants are neither genotyped nor well tagged on existing GWAS arrays. We will use this ExomeChip in an ancestrally diverse population including African Americans (n=7,510), Hispanics (n=5,394) and Native Americans (n=596) from the Women's Health Initiative (WHI). These data will be combined with ExomeChip genotypes and exome sequencing data from 23,303 European Americans and 3,631 African Americans from ongoing WHI studies, for a total of 40,434 WHI participants. This resource will permit us to investigate relationships between low frequency and rare genetic variants with complex diseases of public health importance as well as with well-curated intermediate traits and over 4,800 phenotypic variables available in the WHI. We will develop new methods and apply them in this rich resource to estimate heritability and to identify effects of variants across multiple phenotypes (pleiotropy) and gene-environment interaction which are motivated by our PAGE 1 findings for common variants. Through these efforts, we expect to identify multiple susceptibility loci that may better quantify the proportion of variation in complex diseases explained by genetic variants, identify population-specific loci and provide insights into shared molecular pathways that will more efficiently direct subsequent prevention and treatment strategies in the diverse US population. All genotype and associated phenotypic data will be made publically available through databases, such as dbGaP and as part of the WHI system, building a resource for the scientific community.